Acute Hyperglycemia and Its Impact on Mortality of Acute Coronary Syndrome Patients: A Systematic Review

Acute hyperglycemia or stress hyperglycemia is a frequent finding in patients with acute coronary syndrome (ACS). Several studies have demonstrated the association between acute hyperglycemia with short- and long-term mortality in ACS patients. But the evidence is not concrete. We gathered 1056 articles from three databases, i.e., PubMed, Google Scholar, and Science Direct using different search strategies and filters. We then removed duplicates and 919 articles were screened with title abstract and full text. After a full-text screening of 169 articles, we removed 116 articles. We then applied eligibility criteria and did a quality assessment of articles and finally, we included 21 articles in our study. The 21 articles spanned years 2014 to 2024. Of them, 16 articles were observational studies, two were systematic reviews and meta-analyses, and three were review articles. Six articles used stress hyperglycemia ratio (SHR) alone, seven articles used admission blood glucose (ABG) alone, two used fasting plasma glucose (FPG) alone and one used SHR, ABG, and FPG together as a parameter to measure acute hyperglycemia. Short-term poor outcomes (in-hospital, <30 days) were studied in 12 studies, and long-term poor outcomes (>30 days-1 year, >1 year) were studied in six studies. A positive correlation between acute hyperglycemia and short- and long-term mortality was found in our 21 included studies. The three parameters which are used to quantify acute or stress hyperglycemia in our study, i.e., SHR, ABG, and FPG predict both short- and long-term mortality in ACS patients. Further study is needed to determine the accurate cutoff level of hyperglycemia to be called acute hyperglycemia in diabetics. We tried to review the recent literature on this topic to deepen our understanding of this topic and to provide a base for future research.


Introduction And Background
Acute coronary syndrome (ACS) is a common cause of morbidity and mortality from cardiovascular causes worldwide in the present era [1][2][3].ACS includes two pathologies, i.e., ST elevation-ACS and non-ST elevation-ACS.Non-ST elevation-ACS includes two entities, i.e., unstable angina and NSTEMI (non-ST elevation myocardial infarction).Acute hyperglycemia is a commonly encountered condition in ACS due to neuro-hormonal factors and other factors like beta cell dysfunction, cytokines, and insulin resistance.This acute hyperglycemia or stress hyperglycemia is a strong indicator of poor prognosis in ACS patients by mechanisms not properly elucidated [1][2][3][4][5].
The accurate pathophysiology by which acute hyperglycemia leads to mortality in ACS patients is not elucidated [3][4][5][6][7][8][9][10]. Also, the precise cutoff to call acute hyperglycemia in diabetic and nondiabetic is not specific and varies from study to study.Gaining glucose levels in control through appropriate management strategies can improve outcomes by improving endothelial function, reducing inflammatory and clotting mediators, and reducing infarct size [20].The multifactorial pathogenesis of acute hyperglycemia has brought the need for multiple therapeutic strategies that counteract the factors involved in the pathogenesis of hyperglycemia to improve overall outcomes in ACS patients [20].In this systematic review, we tried to review the studies that have been done in recent years showing the association between acute hyperglycemia and mortality in ACS patients to provide up-to-date evidence regarding this association so that it could broaden our current knowledge on this topic and provide a base for future research.

Review Method
This review has been written following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) [22].

Eligibility Criteria
We included observational studies, systematic reviews, meta-analyses, and review articles.Articles that were in English and studied all-cause and cardiovascular mortality were included.Studies conducted in humans with age of patients above 18 years were included.Book chapters, letters to the editor, case reports, and case series were excluded.Similarly, articles written in a language other than English and articles measuring effects other than mortality were excluded.Parameters like SHR, ABG, and FPG used to quantify acute or stress hyperglycemia were included.Articles using triglyceride glucose index at admission and glucose to glycated albumin ratio to measure acute hyperglycemia were excluded.

Databases and Search Strategy
The literature search was performed in April 2024.We searched three databases; PubMed, Google Scholar, and Science Direct.For PubMed, we used regular search, MeSH (Medical Subject Headings) search, and used filters.For Google Scholar and Science Direct, we used the regular keyword search using Boolean and filters.We selected only the articles relevant to our topic from Google Scholar and Science Direct.We transferred the gathered articles from the three databases to Endnote (Clarivate, London, UK) and from Endnote to Microsoft Excel (Microsoft Corporation, Redmond, WA, USA).Then we removed 137 duplicates.Then we went for screening and quality check.A detailed MeSH search strategy has been presented in

Study Selection
We gathered 1056 articles from the three databases PubMed, Google Scholar, and Science Direct.Among them, 137 duplicates were removed.Then 919 articles were screened with titles and abstracts.In all, 750 articles were excluded and 169 articles were screened with full-text reading.After full-text reading, 116 articles were excluded.Then we applied eligibility criteria to the remaining 53 articles after which 28 articles were removed.Finally, 25 articles were included for quality check.Four articles were removed because of the high risk of bias.A PRISMA flow diagram displaying the number of articles from identification to the number of articles collected for review is presented in Figure 1

Study Characteristics
We have included 21 studies in our systematic review after quality check.The publication year of the articles ranges from 2014-2024.The 21 articles included consist of 16 observational studies, three review articles, and two systematic reviews and meta-analyses.Among observational studies, six were retrospective cohort studies, 11 were prospective cohort studies, and one was a cross-sectional study.One study was a systematic review and meta-analysis and one was a dose-response meta-analysis [1,3].Two observational studies included ACS with comorbidities like triple vessel diseases (TVD) and patients on dialysis [14,17].Hyperglycemia was quantified using different parameters; seven studies used ABG, six studies used SHR, two studies used FPG, and one study used ABG, SHR, and FPG together.Studies used different follow-up periods.We divided the short-term follow-up into in-hospital and ≤ 30 days follow-up and long-term followup into 30 days to ≤ 1 year or > 1-year follow-up.A study characteristics table including author name, date of publication, total participants in each study, follow-up period, mean age of participants, hyperglycemia parameters and cutoffs of each study, glucometabolic status, result, and conclusion of each study is presented below in Tables 2, 3.   Acute hyperglycemia was found to be a significant predictor of mortality with an adjusted OR of 1.81 (95% CI: 1.28-2.55) in multivariable analysis [6].
Higher blood glucose is associated with heightened risk of in-hospital mortality [6].

Participant Characteristics
The total number of patients included in the study was 275061 while 62980 were the total participants of observational studies.Four studies were conducted specifically in STEMI patients, nine studies in acute myocardial infarction (AMI) patients, one study specifically in NSTE-ACS patients, three studies in ACS patients and one study in coronary artery disease (CAD) patients which included ACS patients as well.Among observational studies 17179 patients had diabetes mellitus (DM).Three studies were conducted in non-DM patients, while one study included 2389 pre-DM patients and one study divided DM into DM1 and DM2.Among review studies Alkatiri et al. had 1/3rd cases as DM while Cheng et al. included 24 studies containing DM cases [1,3].Majority of cases in our studies underwent percutaneous coronary intervention (PCI).

Outcome
The main aim of this study was to review the association between acute hyperglycemia with short-and long-term mortality in patients with ACS.The expected outcome was an increase in short-and long-term mortality with increase in blood glucose level.Short-term mortality included in-hospital mortality and ≤ 30 days mortality and long-term mortality include >30 days to ≤1 year and >1 year mortality.

Quality Assessment
We used Newcastle-Ottawa scale for quality assessment of 18 observational stuides and Assessing the Methodological Quality of Systematic Reviews (AMSTAR)-2 scale for four systematic review and metaanalysis.Two cohort studies and two systematic reviews and mataanalysis were excluded due to higher risk of bias.The quality assesment tables for the included 16 observational and two systematic review and metaanalyses are presented below in Tables 4-6.

Acute hyperglycemia and mortality in ACS patients
We analyzed the different parameters used to measure acute hyperglycemia like SHR, ABG, and FPG and their raised level association with short-and long-term mortality in ACS patients.

Acute Hyperglycemia Defined by Stress Hyperglycemia Ratio
Seven studies used SHR as a parameter to quantify acute hyperglycemia.Four studies assessed association with short-term mortality (three in-hospital and one study <30 days and FPG all to be associated with higher in-hospital mortality in STEMI patients [13].Four studies studying the association of SHR with long-term mortality found the association to be statistically significant especially in non-diabetics (p<0.05).

Acute Hyperglycemia Defined by Admission Blood Glucose
Eight studies used ABG as a parameter to measure acute hyperglycemia.Eight studies studied the short-term mortality among which seven in-hospital and one < 30 days mortality.One study used more than year mortality as outcome.All seven studies studying in-hospital mortality found higher ABG to have statistically significant association with in-hospital mortality.Thoegersen et al. found increasing ABG to be associated with 30-day mortality in a dose-dependent manner [11].Paolisso et al. found ABG to be associated with poor long-term outcome in both MIOCA (myocardial infarction and obstructive coronary arteries) and MINOCA (myocardial infarction with no obstructive coronary atherosclerosis) patients [8].Alkatiri et al. found ABG and FPG to be associated with short-term mortality and glycosylated hemoglobin (HbA1c) to be associated with long-term mortality [1].Cheng et al. also found significant association of ABG with short-and longterm mortality [3].

Acute Hyperglycemia Defined by Fasting Plasma Glucose
Fasting plasma glucose (FPG) was used by three studies as a parameter to measure acute hyperglycemia [5,12,13].Upur et al. and Wei et al. studied in-hospital mortality and found FPG to have stastistically significant association with in-hospital mortality in ACS patients [12,13].Gencer et al. found FPG >10 mmol/L to predict one year mortality in ACS patients [5].

Discussion
In this systematic review we reviewed altogether 21 articles from three databases (PubMed, Google Scholar, and Science Direct).Eight studies used ABG, seven used SHR, and three used FPG as a parameter for measuring acute hyperglycemia.Our main finding is that acute hyperglycemia quantified by SHR, ABG, or FPG are predictors of short-term and long-term mortality in ACS patients.Higher SHR has been shown to increase in about-hospital mortality in both diabetics and non-diabetics [15][16][17].The proposed mechanism for acute hyperglycemia in ACS is (1) sympathetic activation and (2) hormonal influence.Sympathetic stimulation leads to release of norepinephrine leading to enhanced gluconeogenesis.Also glucagon is released due to action of norepinephrine and both lead to hyperglycemia [19][20][21].Similarly, during periods of stress cortisol is released which also increases glucose level in blood.There may be pancreatic B cell dysfunction and tissue insulin resistance contributing to hyperglycemia [19,20].Released epinephrine also mobilizes free fatty acids from adipose tissue which contribute to insulin resistance (IR) and decreases muscle glucose uptake [21].
Acute hyperglycemia has an added effect on prognosis of ACS and increases the worse effect of cellular damage caused by myocardial ischemia [20].Although the precise mechanism on how hyperglycemia increases mortality in ACS has not been elucidated but there are certain changes that it brings like increase in free fatty acids increasing arrhythmia risk, increase in reactive oxygen species, decreased functioning of nitric oxide with consequent microvascular and endothelial dysfunction, increased infarct size, reduced collaterals, and vascular inflammation [20,21].Also acute hyperglycemia increases the release of inflammatory and vasoconstrictive factors, increases QT interval,decreases ischemic preconditioning and increases no reflow [19].Stress hyperglycemia in non-diabetic STEMI patients leads to increased incidence of cardiogenic shock, contrast induced nephropathy and mortality [21].

Association Between Acute Hyperglycemia and Short-Term All-Cause Mortality
Ten studies focused on in-hospital mortality and two studies focused on ≤30 days mortality.glucose to be associated with increased short-term mortality in patients with ACS regardless of diabetic status [9,11].Alkatiri et al. found ABG and FPG to be associated with short-term poor outcome in STEMI patients [1].Cheng et al. found admission hyperglycemia to predict higher short-term worse outcome in AMI patients than long-term [3].

Association Between Acute Hyperglycemia and Long-Term Mortality
One study focused on one year mortality and six studies focused on more than one year mortality.Schmitz et al. and Zhang et al. found elevated SHR to be associated with higher long-term mortality; more so in diabetic than non-diabetic [9,17].While Xie et al. and Zeng et al. found elevated SHR to be independently associated with long-term mortality irrespective of diabetic status [14,16].Paolisso et al. found ABG to be an independent predictor of poor outcome in both MIOCA and MINOCA irrespective of DM status [8].Upur et al. found FPG as an independent predictor of long-term mortality irrespective of diabetes [12].Gencer et al. found FPG to be a strong predictor of one year mortality in non-diabetics with ACS [5].
Timely initiation of insulin and other glucose lowering therapy has been shown to decrease morbidity and mortality in ACS patients especially in non-diabetics [20].What is suggested by most studies done till date is acute hyperglycemia in ACS patients is an independent predictor of morbidity and mortality regardless of diabetic status and that timely therapeutic interventions to control blood glucose level can reduce adverse impact of acute hyperglycemia [19][20][21].Also the mechanism behind acute hyperglycemia leading to increased mortality in ACS patients is not precisely elucidated.This topic needs further research in area of cutoff value of acute hyperglycemia in diabetics and non-diabetics for starting therapeutic intervention.Our study may serve as backbone for further studies in future.

Limitations
We were able to review only 21 studies which is slightly less.Similarly we included only free full text articles and also included articles using SHR, ABG, and FPG only to quantify acute hyperglycemia.We conducted review of recently published articles only so that we could provide a up-to-date background on this topic.

Conclusions
From our review, we came to a conclusion that acute hyperglycemia quantified by three important parameters, i.e., stress hyperglycemia ratio (SHR), admission blood glucose (ABG), and fasting plasma glucose (FPG) is a predictor of significant short-and long-term mortality in acute coronary syndrome patients.SHR predicted short-term mortality in both diabetics and non-diabetics while long-term mortality more in diabetics than in non-diabetics.ABG and FPG predicted short-and long-term mortality in both diabetics and non-diabetics.Certain things like the cutoff value for classifying acute hyperglycemia in both diabetics and non-diabetics still remain debatable and differ from study to study.So, further research needs to be done on that matter.We have systematically reviewed recent literatures that will definitely benefit learners and will provide a base for further research.

FIGURE 1 :
FIGURE 1: PRISMA flow diagram.PRISMA: Preferred Reporting Items for Systematic Review and Meta-Analyses.

2 and
associated with an increased risk of all-cause mortality (relative risk: 3.12, 95% confidence interval 2.42-4.02) in a short follow-up.In long-term follow-up also, admission hyperglycemia was associated with an heightened risk of all-cause mortality (1were categorised in to three groups based on ABG as follows: group 1 euglycemic group, admission glucose levels ≤140 mg/dL ( n = 1216); group 2 moderate hyperglycemia group, admission glucose levels > 140 and < 180 mg/dL (n = 370); and group 3 severe hyperglycemia group, admission glucose levels ≥180 mg/dL (n = 112)[4].The in-hospital all-cause mortality risk comparisons between groups 3 and 1 and groups 3 and 2 were statistically significant (OR = 4.595, P<0.001 and OR=3.873,P = 0.006 respectively.More mortality was seen in group of hospital admission[5].A positive corelation was found between hyperglycemia and all-cause death at one year in non-diabetic patients with an unadjusted HR of 2.53 (95% CI 1.10-5.83,p=0.03).The association remained still pertinent in multivariate analysis (adjusted HR 2.39; 95% CI 1.03-5.56,p=0.04).Univariate analysis of diabetic for all-cause mortality was 1.87 (1hyperglycemia was defined as Random Plasma Glucose (RPG) > 200 mg/dl at the time of presentation to the emergency room[6].

TABLE 5 : Newcastle-Ottawa scale for cross-sectional study.
Did the research questions and inclusion criteria for the review include the components of PICO?Yes Yes 2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?Yes Yes 13.Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review?Yes Yes 14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?Yes Yes 15.If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?

TABLE 6 : AMSTAR-2 scale for systematic reviews and meta-analyses.
).Studies like Chen et al. and Xu et al. for in-hospital mortality and studies like Schmitz et al. for < 30 days mortality confirmed statistically significant association of SHR with short-term mortality (p<0.05)[2,9,15].Wei et al. found high SHR, ABG [2,15]t al.found SHR to be a significant predictor of short-term mortality especially in non-diabetics while Xu et al. found SHR to be associated with short-term mortality regardless of diabetic status[2,15].Kumaret al. and Shahid et al. found that ABG as a single most significant predictor of poor in-hospital outcome in ST elevation-ACS regardless of diabetic status [6,10].Ding et al., Paolisso et al. and Zhao et al. also found ABG as a significant predictor of in-hospital mortality in AMI patients regardless of diabetic status [4,8,18].Liu et al. found incidence of death in NSTE-ACS patient without diabetes significantly increased with increased ABG [7].Upur et al. found higher FPG at admission to be associated with increased mortality in AMI patients [12].Wei et al. found ABG, SHR, FPG all to be associated with increased in-hospital mortality in patients with STEMI undergoing PCI [13].Schmitz et al. found SHR and Thoegersen et al. found high admission blood